Multiple bisphosphonates improve BMD in men receiving ADT, including alendronate,54 pamidronate,25,55 ZA,56,57 and neridronate

Multiple bisphosphonates improve BMD in men receiving ADT, including alendronate,54 pamidronate,25,55 ZA,56,57 and neridronate.58 Selective estrogen receptor modulators (SERMs) such as raloxifene59 and toremifene60 have also been shown to improve BMD in this clinical setting. phase III clinic trials demonstrate the emerging role for denosumab in the treatment of prostate cancer bone metastases and prevention VBY-825 of fractures associated with androgen deprivation therapy. = .066); significantly improved 8-year overall survival (22% vs. 14%; HR, 0.077; = .032)CALGB/CTSU 90202680aCastration-sensitive4 mg zoledronic acid versus placebo, every 4 weeks until progression to CRPC or first SRE, then cross over to open labelOngoing Primary endpoint: SRE or prostate cancer death Open in a separate window aTargeted accrual. Abbreviations: CRPC = castrate-resistant prostate cancer; SRE = skeletal-related events Table 2 Randomized Controlled Trials of Osteoclast-Targeted Therapies in Prevention of Bone Metastasis in Nonmetastatic Prostate Cancer .05); increased bone mineral density, decreased breast pain, decreased hot flashes, favorable lipid profile changes Open in a separate window Metastatic Castration-Resistant Prostate Cancer Three randomized controlled trials have evaluated the role of bisphosphonates for patients with bone metastases because of CRPC. Taken together, these trials established ZA as the Food and Drug Administration (FDA)-approved standard-of-care for the prevention of SREs in this patient population. More recently, denosumab was superior to ZA in a phase III clinical trial in this clinical setting, and may become the new standard-of-care. The Zometa 039 Trial Zoledronic acid was FDA approved to treat men with bone-metastatic prostate cancer and disease progression despite first-line hormonal therapy, based on the results of the Zometa 039 trial. In this trial, 643 men with CRPC and asymptomatic or minimally symptomatic bone metastases were assigned randomly to I.V. ZA (4 or 8 mg every 3 weeks) or placebo.33 All men continued ADT and received additional cancer therapy at the discretion of the treating physicians. The primary study endpoint was the proportion of men who experienced 1 or more SRE (pathologic fracture, spinal cord compression, surgery or radiation therapy to bone, or change in antineoplastic treatment to treat bone pain) by 15 months. The study was amended because of adverse renal events (grade 3 increases in serum creatinine). First, ZA was infused over a longer time period (from 5 to 15 minutes) and in greater infusate volume (from 50 to 100 mL). Second, the ZA 8 mg treatment dose was reduced to 4 mg, with serum creatinine monitoring before each dose, and the primary efficacy assessment became the comparison of the 4 mg group versus placebo. After these amendments, adverse renal events between the groups were similar. Zoledronic acid was associated with fewer SREs than the placebo group at 15 months (33.2% vs. 44.2%; = .021). Zoledronic acid increased the median time to first SRE (488 days vs. 321 days; = .009).45 Although median survival was longer in the ZA group than in the placebo group (546 days vs. 464 days; = .091), the study was not designed to evaluate VBY-825 the effect of ZA on survival, and the observed difference in overall survival (OS) was not statistically significant. CGP 032/INT 05 Intravenous pamidronate was examined in men with CRPC and symptomatic bone metastases in 2 similarly designed, multicenter trials, CGP 032 and INT 05, which were pooled and reported together. A total of 350 men VBY-825 were assigned randomly to either pamidronate 90 mg or placebo every 3 weeks for 27 weeks.46 Primary endpoints were self-reported pain, analgesic use, and SREs (defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia). Neither the primary endpoints nor survival differed between the groups. The negative results may have been due to less potent suppression of osteoclast activity, inclusion of subjects with more advanced disease, and use of less precise study endpoints. For Mouse monoclonal to EphB3 example, pamidronate decreased urinary NTx markers of osteoclast activity by approximately 50%, whereas ZA decreases urinary markers of osteoclast activity by 70%-80%.33 NCIC CTG PR.6 Intravenous clodronate was evaluated in 209 men with symptomatic, bone-metastatic CRPC who concurrently received mitoxantrone (12 mg/m2 intravenously every 3 weeks) and prednisone, in the National Cancer Institute of Canada Clinical Trials Group PR.6 study. Patients receiving.